RT Journal Article
SR Electronic
T1 Differential Effects of the 5-Hydroxytryptamine (5-HT)<sub>1A</sub> Receptor Inverse Agonists Rec 27/0224 and Rec 27/0074 on Electrophysiological Responses to 5-HT<sub>1A</sub> Receptor Activation in Rat Dorsal Raphe Nucleus and Hippocampus in Vitro
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 109
OP 117
DO 10.1124/jpet.105.087809
VO 315
IS 1
A1 Renato Corradetti
A1 Boris Mlinar
A1 Chiara Falsini
A1 Anna Maria Pugliese
A1 Antonio Cilia
A1 Carla Destefani
A1 Rodolfo Testa
YR 2005
UL http://jpet.aspetjournals.org/content/315/1/109.abstract
AB The pharmacological properties of cyclohexanecarboxylic acid, {2-[4-(2-bromo-5-methoxybenzyl)piperazin-1-yl]ethyl}-(2-trifluoromethoxyphenyl)amide (Rec 27/0224), and cyclohexanecarboxylic acid, (2-methoxy-phenyl)-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethyl}amide (Rec 27/0074), were characterized using radioligand displacement and guanosine 5′-O-(3-[35S]thiotriphosphate) ([35S]GTPγS) binding assays, as well as electrophysiological experiments, in rat hippocampal and dorsal raphe nucleus (DRN) slices. Both compounds showed a high affinity (Ki, ∼1 nM) and selectivity (&gt;70-fold) at human 5-hydroxytryptamine (5-HT)1A receptors versus other 5-HT receptors. In [35S]GTPγS binding assays on HeLa cells stably expressing human 5-HT1A receptors, Rec 27/0224 and Rec 27/0074 inhibited basal [35S]GTPγS binding by 44.8 ± 1.7% (pEC50 = 8.58) and 25 ± 2.5% (pEC50 = 8.86), respectively. In intracellularly recorded CA1 pyramidal cells, 5-HT1A (hetero)receptor-mediated hyperpolarization, elicited by 100 nM 5-carboxamidoytryptamine (5-CT), was partially antagonized by Rec 27/0224 (∼50%; IC50 = 18.0 nM) and Rec 27/0074 (74%; IC50 = 0.8 nM). In extracellularly recorded DRN serotonergic neurons, Rec 27/0224 and Rec 27/0074 fully antagonized the inhibition of firing caused by the activation of 5-HT1A (auto)receptors by 30 nM 5-CT with an IC50 of 34.9 nM and 16.5 nM, respectively. The antagonism had a slow time course, reaching a steady state within 60 min. Both compounds also antagonized the citalopram-elicited, endogenous 5-HT-mediated inhibition of cell firing. In conclusion, Rec 27/0224 and Rec 27/0074 exhibited inverse agonism in [35S]GTPγS binding assays and differential antagonistic properties on 5-HT1A receptor-mediated responses in the hippocampus but not in the DRN. Whether this differential effect is causally related to inverse agonist activity is unclear. The qualitatively different nature of the antagonism in the hippocampus versus the DRN clearly distinguishes the compounds from neutral antagonists, such as N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-2-pyridinylcyclo-hexanecarboxamide (WAY-100635). The American Society for Pharmacology and Experimental Therapeutics